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 Table of Contents  
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 13-20

Innovations in drug-device combinations for delivering medication to the airways

Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India

Date of Submission26-Mar-2021
Date of Acceptance11-Apr-2021
Date of Web Publication29-Apr-2021

Correspondence Address:
Dr. Jyothsna Manikkath
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/arwy.arwy_15_21

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Airway drug delivery is an effective mode of delivery of drugs for local action in the respiratory tract or for producing faster systemic effect of drugs that have poor oral bioavailability. However, pulmonary drug delivery is incredibly challenging. This article discusses the various types of drug delivery devices, their advantages and limitations. Drugs for pulmonary delivery are typically aerosolised using devices such as pressurised metered-dose inhalers, dry powder inhalers (DPIs), nebulisers, soft-mist inhalers (SMIs) and their variants. The efficiency of drug therapy is influenced both by the drug formulation and the drug-device combination. Further, efficacy of the inhaler and its correct use by the patient are critical issues. Besides the drug component, the incorporation of propellants and other adjuvants in the formulation has been analysed from the perspectives of patient safety and environmental pollution. These devices have evolved with time bringing the advances in technology for use. Feedback mechanisms and particle engineering have been tried and tested.

Keywords: Airways, coronavirus disease 2019, dry powder inhaler, inhaled vaccines, particle engineering, pressurised metered dose inhaler, pulmonary drug delivery, smart inhaler, soft mist inhaler

How to cite this article:
Manikkath J. Innovations in drug-device combinations for delivering medication to the airways. Airway 2021;4:13-20

How to cite this URL:
Manikkath J. Innovations in drug-device combinations for delivering medication to the airways. Airway [serial online] 2021 [cited 2021 Jul 27];4:13-20. Available from: https://www.arwy.org/text.asp?2021/4/1/13/315159

  Introduction Top

The respiratory tract can be divided into upper, central and lower airways. The upper airways comprise the nasopharyngeal and oropharyngeal regions, while the central airways comprise the tracheobronchial region. The bronchioles, alveolar ducts and alveoli make up the lower airways or deep lung. The trachea divides into two main bronchi which then divide into secondary bronchi. These undergo further branching into several generations of bronchioles. The respiratory bronchioles, which are the narrowest airways in the lungs, give rise to alveolar ducts and sacs.[1],[2],[3]

Airway drug delivery

The primary function of the lungs is gas exchange. This is critical for the survival of organisms that respire. Secondary, non-respiratory functions include maintenance of homeostasis, lipid metabolism, active defence mechanisms and interactions with plasma.[4] The airways have typically evolved to remove deposited particles via mucociliary clearance. The respiratory tract, primarily the lung, is also an important site of drug administration.[5]

Inhalation as a mode of drug delivery is noted to have begun with Ayurvedic medicine before 2000 B.C. when the leaves of Datura stramonium and Atropa belladonna were made into a paste and smoked on a pipe.[6],[7] Over the ages, inhalation therapy and pulmonary drug delivery have advanced to include delivery of peptides, proteins and nucleic acids and other agents.[8],[9] The airways have been the primary route of drug delivery for the treatment of pulmonary diseases or for therapeutic action on the airways.[10],[11] This route has certain advantages such as rapid onset of local drug action, reduced systemic exposure and minimal systemic side effects, longer drug action due to lower metabolism in the lung and avoidance of first-pass metabolism or poor gastrointestinal absorption of susceptible drugs.[2],[5],[12]

At present, pulmonary drug delivery is used as the first line of treatment in the case of critical respiratory illnesses such as asthma and chronic obstructive pulmonary disease (COPD)[13],[14] and orphan lung diseases such as cystic fibrosis and pulmonary hypertension.[15],[16] COPD and asthma are projected to be amongst the leading respiratory causes of mortality worldwide, and inhaled medication (importantly corticosteroids) has been found to reduce the morbidity and mortality associated with these diseases.[17],[18],[19]

Drug delivery to the airways and via the airways into systemic circulation

On account of the advantages of the pulmonary route of delivery, it has either been investigated or is in clinical practice for a plethora of drugs for systemic action. These include medication for osteoporosis, diabetes mellitus (types I and II), Parkinson's disease, psychosis, migraine and smoking cessation.[20],[21],[22] Inhaled vaccine delivery has also been investigated, especially to combat respiratory viral infections.[23] Clinical trials for this route for coronavirus disease 2019 (COVID-19) vaccine delivery have been approved at the time of writing of this manuscript.[24]

Drug-device combinations

Drugs for pulmonary delivery are typically aerosolised using devices such as nebulisers, dry powder inhalers (DPIs), soft-mist inhalers (SMIs), pressurised metered-dose inhalers (pMDIs) and their variants. Inhalation medications are also known as ‘combination products’ as they combine both the formulation and a device.[25] Efficiency of drug therapy is influenced both by drug formulation and the drug-device combination. Another factor is the upper airway geometry (altered in disease states) which has a significant effect on oropharyngeal drug deposition.[11],[13] Efficacy of the inhaler device and correct usage of the device by the patient are also critical for effective therapy. Device errors can be classified as critical and non-critical, with the former type being the ones that cause suboptimal therapy.[26] Complexity of the device can also influence user compliance and adherence to medication regimen as many respiratory illnesses are chronic in nature. In conditions such as COPD, adherence <80% was found to be correlated with higher mortality.[27],[28],[29] Therefore, pulmonary disease management guidelines recommend individualisation of inhaled therapy and monitoring of the inhaler technique for each patient.[30]

  Pressurised Metered-Dose Inhalers Top

Introduction of the metered-dose inhaler (MDI) or pMDI was a breakthrough in respiratory drug delivery. MDIs were pioneered by Riker Laboratories, Inc., (now 3 M Drug Delivery Systems) in 1956.[9] Since then, the pharmaceutical aerosol industry witnessed significant growth and the introduction of innovative inhalers improved the quality of life of several individuals across the globe.[31] Pressurised MDIs comprise a pressurised canister, from which the drug (in solution or suspension form) is actively expelled with a propellant. The device also consists of a metering valve, which delivers a consistent amount of micronised drug with each puff, and an actuator mouthpiece that atomises the formulation into heterodisperse aerosol droplets.[32] Apart from propellant, cosolvents and surfactants such as lecithin or sorbitan trioleate are routinely added to reduce particle aggregation in the formulation.[33] The advantages of pMDIs include multidosing, rapid and consistent drug delivery, low chances of microbial contamination, cost-effectiveness and ease of use.[28] These devices do have some limitations. Significant amongst these is suboptimal therapy arising from weak grip strength of the patient, leading to the failure of coordinating actuation and inhalation, resulting in low dose of drug delivered to the lungs.[34],[35] The CRITical Inhaler mistaKes and Asthma controL Study identified this lack of coordination between actuation and inhalation in 24.9% of individuals using a pMDI.[36] User training was also found to be important with pMDIs. One study found that without training, >85% of patients failed to use their pMDI inhaler properly.[37]

Innovations in pressurised metered-dose inhaler technology

Spacers and valved-holding chambers

To overcome the issues with actuation-inspiration coordination, spacers and valved-holding chambers (VHCs) were introduced in the pMDI design. These additions can also reduce the possibility of oropharyngeal drug deposition and its potential adverse effects such as throat irritation, dysphonia and oral candidiasis found with the use of corticosteroids. VHCs are spacers with one-way valves which regulate inspiratory flow and prevent the expulsion of moisture-laden gas into the spacer. They decrease the velocity of the emitted aerosol, reduce aerosol dispersion on delayed inhalation and increase the aerosol delivery to lungs.[38],[39] Spacers/VHCs for emergency administration of bronchodilators in asthma/COPD exacerbation have been found to produce similar efficacy and safety as nebulisers.[40] Certain VHCs have an exhalation valve which prevents re-inhalation and allows comfortable breathing. Some may also be fitted with a facemask for use in acutely ill, consciousness-altered or uncooperative patients. There have been several developments in facemask technology and they are now optimised to reduce dead space, minimise inadvertent drug deposition on the face and eyes and to fit the patient comfortably.[41]

The use of spacers and VHCs is not without its drawbacks. The added bulk of the spacer makes such MDIs less portable and less ready for immediate inhalation. It also adds to the cost of the device and makes it less user friendly for aged patients who may have difficulties in assembling the system.[14] Spacer walls can also retain some drug which makes it difficult to discern the actual dose of drug delivered to the lungs. Moreover, the dose output is dependent on the combination of pMDI and spacer/VHC selected.[42]

Breath-actuated metered-dose inhaler

These devices are activated by the user's inhalation which leads to release of the drug dose. These operate even at low respiratory flow rate and help overcome the issue with coordination of breathing and actuation. These are demonstrated to be easier to use and provide better disease control than conventional MDIs.[43] The first breath-actuated MDI (baMDI) was the Autohaler commercialised by Riker in 1970 (isoproterenol hydrochloride and phenylephrine bitartrate).[9] Latest developments in baMDI technology permit activation of the device at significantly low flow rates (27–30 mL/min), high fine-particle fraction and consequently, high rates of pulmonary drug deposition.[14]

Modification of propellant

Older pMDIs contained chloroflurocarbon (CFC) propellants which produced the ‘cold Freon’ effect and relatively high deposition of drug in the throat, inducing cough, discomfort and bronchospasm. The cold Freon effect involves the cold blast of the propellant that may cause the user to stop inhalation or inhale via the nose. CFCs are also documented to be detrimental to the earth's ozone layer and are thus not environment friendly. Innovations in pMDI technology have replaced CFCs with hydrofluoroalkane (HFA) propellants.[33] These give warmer sprays than the CFC propellants and partly overcome the cold Freon effect. HFAs that have been investigated in pMDIs include HFA-134a (tetrafluoroethane), HFA-227ea (heptafluoropropane) and HFA-152a (1,1-difluoroethane). Amongst these, HFA-152a has demonstrated better performance than the other HFAs with respect to suspension settlement and resuspension behaviour of some drugs, even in the absence of additional excipients.[44]

Designs for enhancing medication compliance

Another innovation with pMDIs has been the introduction of mechanical dose-counters, which prevent patients from using the device beyond the set number of doses, thereby preventing suboptimal therapy. Yet, another development with pMDIs is the ‘intelligent inhaler’ which deploys a microprocessor to control the inhalation and adherence to therapy.

  Dry Powder Inhaler Top

DPIs were first mentioned in Vincent Alfred Newton's UK patent 1161.[7] Nearly a century later, Abbott launched their Aerohaler for the administration of penicillin and norethisterone. Most early DPIs were developed for delivering low doses of drugs. With the FDA approval of Tobi Podhaler (of Novartis) in 2013, it was demonstrated that DPIs can be used to deliver high drug doses (28 mg in this case).[45],[46] In many of the early devices, gelatin capsules were the dose container, and the drug powders were formulated with lactose as the diluent.[7] DPIs use the inspiratory force produced by the patient to both extract the drug powder from the drug compartment and to disaggregate the powder into respirable particles.[35],[47] These devices do not require actuation-inhalation coordination. Besides, as they do not employ propellants such as in pMDIs, issues with CFCs are avoided. Other advantages of DPIs include enhanced drug stability (as it is in dry form), easier formulation of poorly-water soluble drugs, simultaneous administration of multiple drugs (in dual-and triple-drug DPIs), multiple dosing, portability, ease of use and low cost.[7],[11]

Most DPIs developed before 2010 were passive breath-operated devices, requiring high flow rates (>60 L/min) to disaggregate the particles. This proved to be difficult for COPD patients who were unable to produce necessary inspiratory flows.[48] Furthermore, inspiratory flow rates are lower for females and reduce with age.[49] However, over the last decade, DPIs have been developed that are activated at inhalation flows of 30 L/min or lower.

Power-assisted dry powder inhalers

DPIs independent of patient attributes and inhalation flow would be preferred.[50] Power-assisted DPIs are a new form of DPI that can be activated to disperse the drug powder using an extrinsic source of energy instead of relying on the patient's inspiratory flow. They mostly incorporate battery-driven impellers or piezoelectric crystals for dispersing the powder. Although these devices could be of immense benefit to patients, they have not been launched into clinical practice.[51]

Micro- and nanoparticles in dry powder inhalers

Particle engineering has been the cornerstone of drug delivery using DPIs.[7] This includes particle size, surface morphology, aerodynamic diameter, degree of crystallinity, water content and interparticulate interactions including electrostatic interactions, Van der Waals forces, mechanical interlocking and capillary condensation.[11] All these factors affect the aerosolisation of the drug powder in the DPI. One of the most important consideration is the particle size,[52] and it has been found that particles >5 µm tend to get impacted and deposited in upper airways. For targeted drug deposition in smaller airways, mass median aerodynamic diameter of 1–3 µm for drug particles have been found essential.[53] This has led to the development of several micro- and nanoparticulate drug carriers. Particles smaller than 0.5 µm initially get deposited in deep alveolar regions but can be easily exhaled on account of their small size.[4] Therefore, these carriers are tuned for particle characteristics and release kinetics to ensure longer drug retention, protection of drug from the local biological environment and potentiation of the therapeutic benefits.[54] These carriers include nanocrystals, lipidic carriers, nanocomposites, nanoaggregates, polymeric nanoparticles, dendrimers and microparticles.[54],[55],[56],[57],[58] Nanoparticles of sizes <50 nm can be formulated as micron-scale dry powders which disintegrate into individual subunits after contacting the lung, thereby preventing exhalation of the particles. Such formulations are particularly relevant for infections such as pulmonary aspergillosis, where the Aspergillus conidia penetrate deep into the lungs and require drug administration at that site.[53]

  Nebulisers Top

Nebulised drugs are generally administered via oral administration or using either invasive or noninvasive ventilation.[59] These have a complex setup and are cumbersome to use and usually associated with poorer rates of compliance and higher health-care costs than pMDIs, DPIs or SMI.[27] Therefore, they are used generally in patients who cannot effectively use pMDIs or DPIs. Studies have found that vibrating mesh nebulisers produce higher drug delivery efficiency than conventional jet nebulisers. However, mesh nebulisers present problems with clogging of the mesh by particles, and newer technologies have evolved to overcome this. The drug delivery efficacy from nebulisers can be improved by refining the process of nebulisation or using secondary devices and technologies with the existing device to achieve modified aerosol size distribution, coordinate inhalation with aerosol delivery, improve the user interface, and reduce drug loss due to deposition in the device.[59]

Another innovation is the development of an adaptive aerosol delivery system which controls the aerosol emission on the basis of the user's breathing pattern. Along with feedback to the patient, it also promotes medication adherence.[60]

  Soft-mist Inhaler Top

SMIs are propellant-free multiple-dose devices which utilise liquid formulations similar to nebulisers. These devices deploy a coiled spring which can be compressed by the user. Release of the spring provides mechanical energy which generates the aerosol. The drug solution is forced through a series of nozzles, while a unique system disintegrates this into inhalable droplets.[61] Unlike pMDIs, there is no propellant used in the formulation. Furthermore, the velocity of the soft-mist emerging from the nozzles is lower than that from pMDIs, reducing the possibility of oropharyngeal particle deposition. Furthermore unlike DPIs, high inspiratory flows are not required.[62] In spite of its advantages, one study found 30% higher mortality from an SMI compared to a single-dose DPI (HandiHaler) in COPD patients, although the study was not conclusive as to the cause.[63] Yet, another study found a 52% higher risk of mortality in COPD patients with the use of tiotropium SMI.[64]

  Smart Inhalers Top

These are inhaler devices incorporating electronic components for the purpose of improving medication adherence. They can be connected to other electronic devices such as smartphones using technologies such as Bluetooth® to remind the user of the next dose and provide continuous monitoring of the patient's technique, timing and usage of the inhaler.[27],[65] Integrated acoustic or pressure sensors can detect inhalation flow changes correlating with lung function. They can also record the interaction of inhaler and environment using geo-location to identify environmental triggers such as pollutants and allergens, promoting self-management of the particular disorder.[66] The ‘smart’ component of the inhaler can be integrated as an add-on module with an existing inhaler or it can be integrated originally with the device itself.

The STudy of Asthma and Adherence Reminders trial investigated medication adherence in children with asthma. This study found that electronic versions of pMDIs and Turbuhaler, which integrated a feedback-system for inhaler reminders, produced higher medication adherence (70%) compared to the control group (49%).[67] Another clinical trial that compared asthma patients receiving inhaler reminders with feedback found lower rates (11%) of ‘severe exacerbations’ of the disease compared to those without the feedback (28%).[68]

  Inhaled Treatment for COVID Top

At present, we are witnessing a massive global health crisis in COVID-19. The epidemic has worsened and affected global health and economies. Patients with severe infection develop progressive respiratory failure.[69] Several therapeutic agents such as remdesivir, lopinavir/ritonavir, favipiravir, nafamostat mesylate, hydroxychloroquine, darunavir/cobicistat, camostat, eculizumab, tocilizumab, colchicine, baricitinib and aviptadil have been investigated for treating this infection.[70],[71] Inhaled medication, especially nitric oxide and corticosteroids, has been demonstrated to provide benefit in the management or protective effect against this infection.[72],[73],[74] Nebulised medication such as interferon IFN-κ/trefoil factor 2 (TFF2), interferon beta-1a, heparin, tissue plasminogen activator, budesonide, ciclesonide and ivermectin have also shown promise.[75],[76],[77],[78],[79] However, use of nebulised drugs with this infection is fraught with risks due to the possibility of generation of high amount of respiratory aerosols which can disperse viral particles in exhaled air. It has been found that chances of transmitting the infection to health-care workers are higher with nebuliser use. Therefore, recommendations suggest the careful use of nebulised medication and appropriate controls including high efficiency particulate air filters to limit disease spread.[80],[81],[82] As it is primarily a respiratory infection, individuals with COPD and asthma are at a higher risk to contract this disease.[83] If bronchodilators are required in suspected or confirmed cases of COVID-19 infection, it may be preferable to use pMDIs with spacer or VHCs instead of nebulisers.[3],[84]

  Summary Top

Inhaled and pulmonary drug delivery are important noninvasive modalities that can improve therapeutic outcomes for a wide variety of drugs for both local and systemic use. Most inhaled medication is delivered via devices which is critical for successful therapeutic outcomes. Over the past years, newer technologies have bettered the performance of the devices and have evolved to synergise with the drug formulations. Respiratory diseases are by themselves complex, besides being unique to each individual. While there may not be one size that fits all, a device could be selected on the basis of the particular disease to be treated, age of the user and ability to handle the inhaler device and urgency of delivering the medication. Along with technological innovation, cost and patient-friendliness are important considerations from the point of view of the physician and the patients.

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Conflicts of interest

There are no conflicts of interest.

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